Project Summary/Abstract Non-Hodgkin lymphoma in women: reproductive, hormonal and genetic factors Non-Hodgkin lymphoma (NHL) is the most common hematopoietic cancer in U.S. adults and has a higher incidence in men than in women (ratio of 1.4:1). Although several studies have investigated the association between reproductive factors and exogenous sex-hormone exposures to explain this sex differential, results have been varied and no comprehensive assessment of relevant epidemiologic and genetic factors related to risk of NHL and NHL subtypes has been conducted. Our innovative analyses will leverage NCI funding by using epidemiologic and genetic data already collected in our large population-based case-control NHL study (2055 cases, 2081 controls) to: Aim 1) determine whether endogenous and exogenous hormone exposures in women are associated with risk of NHL and common NHL subtypes and;Aim 2) determine whether single nucleotide polymorphisms (SNPs) in genes related to steroidogenesis or that function in the same immune- related biologic pathways as sex-hormones, alter the association between factors in Aim 1 and risk of NHL and NHL subtypes. SNPs in sex-hormone genes of interest include estrogen receptors (ESR), cytochrome P450 17A1 (CYP17A1), sex-hormone binding globulin (SHBG) and catechol-O-methyltransferase (COMT), and in immune/inflammatory pathways include interleukins (IL), nuclear factor kappa B (NF-:B), tumor necrosis factor alpha (TNF-1) and lymphotoxin alpha (LTA). Risk of NHL also has been associated with increased body mass index (BMI) and some autoimmune conditions with each in turn associated with levels and circulation of sex- hormones. Therefore, BMI and autoimmune conditions will be carefully assessed as potential confounders and effect modifiers of the association between hormonal effects and NHL risk. Parsimonious multivariable unconditional logistic regression models will be used to obtain odds ratios as estimates of relative risk. Gene- environment interactions will be evaluated for exposures and SNPs in genes that function in the same biologic pathways, e.g. pregnancy-related factors, and SNPs in IL-10, TNF-1, ESR1 and ESR2. False discovery rate methods will be used to control for multiple hypothesis testing. The study's major strengths are: 1) DNA already analyzed for SNPs in 146 genes in biologic pathways that may be relevant to the association between sex-hormone s and NHL susceptibility;2) already collected rich epidemiologic dataset including extensive reproductive history, sex-steroid hormone use, autoimmune conditions and BMI available to evaluate main effects, confounding and effect modification;5) pathological confirmation and NHL subtype classification using the WHO classification;6) data will be pooled for future analyses within the InterLymph Consortium allowing analyses of rare subtypes and exposure. Clarifying the role of these sex-hormone related factors in NHL risk will improve our understanding of lymphomagenesis, generate hypotheses for future research and be directly applicable to screening and prevention programs to reduce NHL incidence. PUBLIC HEALTH RELEVANCE: Project Narrative Incidence of non-Hodgkin lymphoma (NHL) is higher in men than in women and few risk factors have been established other than those associated with severe immunosuppression and some rare genetic conditions. Given that sex-hormones impact immune function, it is plausible that hormonal-related exposures and conditions that differ between women and men may help explain the observed sex-difference in NHL. Analyses that clarify the association among reproductive factors, use of estrogen-related therapies and risk of NHL and NHL subtypes in women and whether the relationship between NHL risk and sex-related hormones is altered by variation in genes important in hormone metabolism/production and immune function will improve our understanding of NHL development, help to generate new hypotheses for future research and will be directly applicable to prevention, intervention and screening programs with a goal to reduce NHL incidence.